Cancers are the second most prevalent cause of death in the United States, causing 450,000 deaths per year. One in three Americans will develop cancer, and one in five will die of cancer. While substantial progress has been made in identifying some of the likely environmental and hereditary causes of cancer, there is a need for additional diagnostic and therapeutic modalities that target cancer and related diseases and disorders. In particular, there is for a need a greater understanding of the various biochemical pathways that are involved in disregulated cell growth such as cancer as this will allow for the development of improved diagnostic and therapeutic methods for identifying and treating pathological syndromes associated with such growth disregulation.
With 32,000 new cases (representing an annual increase of 2%) and 12,000 cancer related deaths every year (see, e.g. Jemal, A. et al. Cancer statistics, 2004. CA Cancer J Clin 54, 8-29 (2004)), kidney cancers represent a major oncological therapeutic challenge. Standard chemotherapy agents have not been useful, and biologic agents such as interleukin-2 and interferon have shortcomings due to their toxicity profiles and the low meaningful response rates. Systemic chemotherapy produces few and only transient responses in patients with metastatic (i.e. advanced) kidney cancer. Given these limited treatment options, the results of the Phase II clinical trial using CCI-779 in patients with advanced kidney cancer, which found objective response rate of 7% and a disease stabilization rate of approximately 50% are intriguing, especially as there is no current molecular insight into the these group of patients who have mTOR dependent tumors (see, e.g. Atkins et al., J Clin Oncol 22, 909-18 (2004)). The parallels to the recent EGFR inhibitor trials in unselected lung cancer patients are striking. EGFR inhibitors (Iressa, Tarceva) have low, but consistent single agent objective response rates in refractory lung cancer.
Successful translation of kinase inhibitor compounds from the laboratory to the clinic depends on identifying subsets of patients most likely to benefit from them. A key is to this is identifying kinase dependent tumors (see, e.g. Sawyers et al., Genes Dev 17, 2998-3010 (2003)). Most of the kinase inhibitors in clinical practice at present work on the paradigm of directly targeting the kinase mutation, e.g. BCR-ABL and Receptor Tyrosine Kinase (RTK) mutations/ligand overexpression, resulting in constitutive activation of downstream signaling molecules. These pathways can also be indirectly activated by loss of negative regulators, resulting in kinase activation, i.e. loss of PTEN and subsequent activation of the PI3K/AKT/mTOR cascade (see, e.g. Neshat et al., Proc Natl Acad Sci USA 98, 10314-9 (2001)). Prostate and brain tumors, which have tie highest mutation rates of PTEN, exhibited enhanced sensitivity to mTOR inhibitors, solidifying the proof of concept. Oncogenic dependence on this signal transduction pathway with subsequent inhibition of mTOR paralleled a “synthetic lethal” mode of action. Interestingly, CCI-779, a mTOR inhibitor, shows promising antitumor activity in advanced kidney cancers, with approximately 7% of patients showing objective response rates and disease stabilization in approximately 50% of patients (see, e.g. Atkins et al., J Clin Oncol 22, 909-18 (2004)). Based on preclinical data generated in prostate and brain tumors, this increased sensitivity could possibly be explained by the loss of the PTEN tumor suppressor gene. A potential drawback to this hypothesis however is the low incidence of somatic PTEN mutations in renal cancers. In addition, there are no known mutations of mTOR in kidney cancers.
As noted above, while researchers have identified a variety of genes and pathways involved in pathologies such as cancer, there is need in the art for additional tools to facilitate the analyses of the regulatory processes that are involved in disregulated cell growth. Moreover, an understanding of how the products of genes involved in disregulated cell growth interact in a larger context is needed for the development of improved diagnostic and therapeutic methods for identifying and treating pathological syndromes associated with growth disregulation. In particular, there remains a need to identify signal transduction events driving oncogenesis and to identify markers useful for assessing progression or inhibition of the oncogenic phenotype.